21-methyl and 21-hydroxymethyl steroid compounds



United States Patent 3,234,095 ZI-METHYL AND ZI-HYDROXYMETHYL STEROID COMPOUNDS Eugene J. Agnello and Gerald D. Laubach, Lyme, Conn.,

assignors to Chas. Pfizer & (10., Inc., New York, N.Y.,

a corporation of Delaware N0 Drawing. Filed June 19, 1963, Ser. No. 288,880

7 Claims. (Cl. 167-77) This application is concerned with new and useful steroid compounds. with certain steroids having adrenocortical activity characterized by having unique chemical features in the carbon atoms side chain at the 17fi-position. It is concerned also with a method of making these valuable compounds and with pharmaceutical compositions containing them together with pharmaceutically-acceptable excipients.

This application is a continuation-in-part of previously filed patent applications Serial Nos. 740,600, 764,272, 764,273, 800,992 and 3,996, filed June 9, 1958, September 30, 1958, September 30, 1958, March 23, 1959, and January 22, 1960, respectively, all now abandoned. It should be noted that the system of nomenclature used herein is different from that employed in the previous abandoned applications. Itis felt that the present system is in more strict conformance with preferred practice.

Compounds within the purview of this invention include those having the formula: Y

More particularly, it is concerned- 3,234,095 Patented Feb. 8, 1966 R is hydrogen, fluorine, chlorine or methyl; R is hydrogen or hydroxyl; R is hydrogen or acyl, said acyl group being derived from monoand dicarboxylic acids containing up to ten carbon atoms; and R is CH3 OH C C or ORo l I i wherein R is an acyl group derived from monoor dicarboxylic acids containing up to ten carbon atoms and containing only carbon, hydrogen and oxygen. The Water solubility of the compounds derived from dicarboxylic acids is enhanced by conversion to alkali metal or alkaline earth metal salts by reaction with a suitable base such as sodium carbonate or calcium hydroxide. The water solubility of compounds derived from amino carboxylic acids is enhanced by conversion to acid addition salts by reaction with a suitable acid such as hydrochloric acid or sulfuric acid. These salts are included within the purview of this invention. In the above structures, X is hydrogen, whalogen, a-methoxy or u-ethoxy, Y is keto or fi-hydroxyl. In the above structures, at least three of R R R and the additional substituent on a hydrogen substituted number sixteen carbon atom is always hydrogen.

Also included within the preferred compounds of this invention are further compounds in which hydroxyl groups at the 16- and 17-positions are derivatized with aldehydes or ketals known generically as acetonides, in this case 16u,17a-acetonides. The acetonide moiety of preferred compounds of this invention contain from two to nine carbon atoms.

The acetonides within the purview of this invention are prepared by procedures well known to those skilled in the art. They may be prepared, for example, by the procedure described by Woodward et al. in the Journal of the American Chemical Society, 74, p. 4241 (1952). In this procedure, the steroid compound is taken up in the carbonyl compound, for example, acetone, methyl ethyl ketone or di-n-butyl ketone which has been dried over a suitable drying agent such as anhydrous potassium carbonate. Anhydrous copper sulfate is added and the mixture agitated for from about 24 to about 48 hours. The mixture is then filtered and the desired product recovered, for example, by removal of the solvent in vacuo. Other methods of forming acetals and ketals are also applicable. For example, the steroid may be taken up in the liquid aldehyde or ketone and refluxed in the presence of a catalytic amount of a mineral acid such as concentrated hydrochloric acid, for from about 1 to about 10 minutes. The desired product is precipitated by the addition of water.

Starting compounds used in the preparation or the valuable compounds of this invention include steriod compounds substituted at the l7 8-position with a halosubstituted hydroxylated propanoyl group such as 0:,-

hydroxy-fi-halo-propanoyl and .a-halo- 3-hydroxy pro-panoyl wherein the halo group is 'bromine or iodine. These compounds are prepared in accordance vwith the, procedure fully described and illustrated in co-pending and concurrently filed patent application, Serial No. 3,998, now Patent No. 3,031,375.

The following sequence shows the preparation of A -pragene-1 1,8,17a,2l-triol-3,20-dione one of the com-, pounds of this invention. It is equally applicatble to the preparation of other compounds within thepscope of the invention.

In the above compounds, Z is a bromine or iodine.

It will be noted from the above structures thatJthe presence of a new asymmetric center at.-C2l gives rise to'the possibility of two epimers.

This sequence of reactions and the intermediate prodnets are described and claimed in copending and concurrently filed patent applications Serial'Nos. 3,998, now= 55 444. The requisite aldehydes are prepared from they; corresponding 21 hydroxylated co'mpoundsiby reaction with cupric acetate as described in=UJSwPatent2,773,078

Patent No. 3,031,375, and 3,999, now' Patent No. 3,031,-

issued December 4, .1956;

The epoxide is prepared byreaction of the aldehyde with diazomethane in a reaction inert solvent at a tem-- perature of from. about 0 C. to about 25 C. for aperiod of from about 1 to. about 24 hours.

The desired bromo or iodo'hydrin is preparedby re-.

action of'the epoxide with hydrogen bromide or iodide,

preferably in equimolar quantities, in a reaction inertorganic solvent at a temperature of from about-15 C;

to about 30 C. for a period of from about 15 minutes to about 4 hours.

As previously stated,'the products of this invention having the-asymmetric center at C-21 exist in epimeric forms. In accordance with the method of synthesis described herein, both epi-rners are obtained. 'Both epimers are active, and of course the mixture is active, so that: for most th peutic purposes it is immaterial whether a mixture or a particular epimeris employed. It is rarely necessary to separate" the isomers, but this can be accomplished, if desired, using standard well-known methods For example',.the 2l-alcoho1s can be separated by paper chromatography using .chloroform as the mobile Each.

phase and formarnide :as the stationary phase. product may be; isolated :by dissolving it from the paper usin-ga suitable solvent such as ethyl acetate "or chloroform.

Thespecific epimers may also bed-prepared and iso lated. The B-isomer'is prepared by reduction of the pyruvoyl compoundsdescribed.andclaimed in copending and Econcurrently filed. patent application, Serial No. 4,000,- now. US. Patent No. 3,093,665, with. yeast or withialkali metal hydrides as illustrated below. The A-tand B-isomer may1 be separately preparedand isolated?v by the method: described and claimed inycopendingand. concurrently filed patent application Serial No. 3,995," now U.S.Patent No. 3,045,010.. This procedure .isalso illustrated in the examples.

'For the preparation of the valuable .compounds of this invention, the steroid compound. with t the.v side chain bromohydrin :oryiodohy drin functionv is treated with a debrorninating ordeiodinatingtgagent such as zinc andacetic acid, or zinc and. ethanol or other lowervalkan'olfl Reductive dehalogenationrwith Raney nickel. isalso ap-. plicable. Both procedures are illustrated below.

Suitable solvents for carrying, out; the reaction with Raney nickel; include reaction inert organic solvents such as lower aliphatic oxygenated solventsrincluding 'ethers',

alcohols, acids and ketones containing upto .five carbon: atoms. Methanol, ethanol, propanol,--isopropanol, pen-.

tanol, acetone, methyl isopropylketone,dioxane, acetic acid and p-ropionic acid are examples of suitable solvents The use of a mixed solvent suchias methanol-acetic acid.

issometimes advantageous. w The. amount of Raneynickel used is not critical although to insure the mosteconomical utilization of the" steriod starting material, iit is generally preferred to use an=excess of. this dehalogenating :agent; From four to'.

twenty grams of Raney nickel per gramof steroid starting material hasubeen found to provide suitable yieldsi The. preferred excess, as will be recognizediby. those skilled in the. art, will depend upon the degree of activity; of the Raney nickeL This in turn Will;depend upon its previous treatment. With Raney nickel which has been: washed first. with water, then withacetic acid, then with -methanol, and,.finally with: acetone in accordance with known procedures it is usually ,found that from ten to fifteen grams of Raneynickelper. gram ofsteriod givesuitable results. However, .:the Raney nickel cangbe. used without previous treatment :or with other known 1 treatments and stillfunction asa dehalogenating agent for thebromohydrin or iodohydrin.

The .duration of the reaction is; not criticalidepending 7 only upon the degree .of activity' of the Raney nickel.

This degree, ;of activity is; readily determined by tests well known to=those skilled in the .art, and include, for

example, the; reduction of known compounds requiring H varying degrees of reducing activity. Reaction periods 7 as short as five minutes and as long as twenty-four hours have be'en used. Iti is, however, generally found that suitable-yields' can be obtainedusing a reaction period.

of frorn five,,minutes to two hours.

a For optimum yields the temperature of :the reaction shouldbe controlled so that it does not rise above 30" C. during thereaction period and Eit iS -best tov carry out the reaction between .0 C. and 15 C.

Althoughi'it is not essential, it is preferred ,to carry: out the reaction in an inert atmosphere such as a nitrogen; atmosphere. This assures the most eflicient use of the. Raneynickel by minimizing its reaction with atmospheric:

oxygen;

The, desired productcan be isolatedafter removal of thetRaney nickel by simplyevaporating the solvent and purified .byrecrystallization from a suitable solyent sue];

5 as ethyl acetate. It can also be purified by trituration with a suitable wash liquid such as ethyl acetate or etherethyl acetate.

If the solvent used is a lower aliphatic acid or a mixture containing such an acid it may be desirable to neutralize the acid with an alkaline reagent such as ammonium or sodium hydroxide and to isolate the active compound by extraction from the neutralized aqueous mixture with an organic solvent. Suitable extraction solvents include water immiscible lower halogenated alkanes such as ethylene chloride, chloroform and carbon tetrachloride, or ketones such as methyl isobutyl ketones. The product is isolated from the extraction solvent and purified as described above.

The biologically active compounds of this invention may be administered alone or in combination with acceptable pharmaceutical carriers, the choice of which is determined by the preferred route of administration, the solubility of the compound and standard pharmaceutical practice. In general, the dosage of these compounds is of approximately the same order of magnitude as the dosage of hydrocortisone, and these compounds are useful to treat the types of pathological conditions often treated with hydrocortisone. Because of their great adrenocortical activity it is sometimes possible to use dosages of these compounds which are lower than those of hydrocortisone.

For oral administration the compounds may be administered in the form of tablets containing excipients such as starch or milk sugar. Aqueous suspensions and elixirs which may be sweetened or flavored may also be used. To apply these therapeutic agents topically, they may be prepared in the form of ointments and salves in suitable bases especially non-aqueous petrolatum type bases. For intra-articular injection aqueous suspensions may be employed. In this case various suspending and wetting agents may be added to the compositions to obtain a suspension not tending to settle out easily or to pack down in the bottle in which it is stored. Intra-muscular and subcutaneous dosage forms may also be prepared by standard pharmaceutical practice.

Among the compounds contemplated by the instant invention are those which hear an acyl group at the 21-position, said acyl group being derived from amino carboxylic acids containing up to ten carbon atoms. Special mention is made of the 2l-diethyl aminoacetate esters of steroids bearing a methyl group on the 21-position. Particularly noteworthy are the ZI-diethylaminoacetate esters of 6afluoro-2l-methyl-A -pregnadiene-l1,8,17a,21-triol 3,20 dione and 6oz,9a-difiuoro-2l-methyl-A -pregnadiene-115, l7a,2l-triol-3,20-dione and the acid addition salts thereof, such as the hydrochlorides.

These may readily be prepared from the 2l-hyroxyl compounds of the instant invention by procedures -to be exemplified in detail hereinafter. An especially convenient sequence involves conversion of the Zl-hydroxyl group to an amine-reactive acyl group, among which may be mentioned the 2l-chloroacetate, and then treatment of the amine-reactive acyl group with an appropriate amine. The 2l-acyl derivative of the amino carboxylic acid thus obtained can be converted to its acid addition salts by treatment with the desired acid according to procedures to be exemplified hereinafter.

The following examples are given solely for the purpose of illustration and are not to be construed as limitations of this invention, many apparent variations of which are possible without departing from the spirit or scope thereof.

Example I .--21 -methyl-A -pregnadiene-1 1 8,1 70:,21 trial-3,20-dine A solution containing 500 mg. of 2l-bromomethyl-A pregnadiene-l1fi,'17u,21-triol-3,20-dione in 200 ml. of absolute methanol was cooled to 0 C. and 5 g. of Raney nickel in 50 ml. of methanol was added. The mixture was 6 stirred for two hours, filtered and the methanol removed by evaporation. The residue was triturated with a 1:1 mixture of ethyl acetate and ether. The product was recovered by filtration.

Example ll.21 hydroxymethyl A regnadiQne-I 1,8, 1 7u-dz'0l-3,20-di0ne A solution containing 500 mg. of 2l-iodo-2l-l1ydroxymethyl- A -pregnadiene-IlB,l7a-diol-3,20-dione in 200 m1. of dioxane was cooled to 30 C. and a mixture containing 20 g. of Raney nickel in ml. of dioxane was added. The reaction vessel was flushed with nitrogen and the mixture stirred for five minutes. The mixture was filtered, the solvent removed in vacuo and the residue triturated with 1:1 ethyl acetate in ether. The desired product Was recovered by filtration.

Example 1II.21 methyl M-pregneneJ 15,1 7a,21lri0l- 3,20-di0ne A solution containing 500 mg. of 2l-iodomethyl-A pregnene-l1,8,l7a,21-triol-3,20-dione in 100 ml. of isopropanol was cooled to 10 C. and a mixture containing 4 g. of Raney nickel in 50 ml. of isopropanol was added. (The Raney nickel had been previously washed with water and then with diluted acetic acid to a pH of 7. It was then washed with methanol, the methanol removed and the Raney nickel refluxed for 30 minutes in acetone.) The reaction mixture was stirred for 15 minutes, filtered and the solvent removed in vacuo. The desired product was triturated with 1:1 ethyl acetate and ether and recovered by filtration.

The corresponding 21-hydroxyme-thyl compound was similarly prepared from 2l-bromo-2l-hydroxymethyl-M- pregnene-1 1B,17a-diol-3,20-dione.

Example I V.-2I methyl-A -pregnatriene-1 1,8,1 701,21-

trial-3,20-di0ne A solution containing 500 mg. of 21-iodomethyl-A pregnatriene-1 1fi,17u,21-triol-3,20-dione in a solvent mixture containing 50 ml. of glacial acetic acid and m1. of methanol was prepared. It was cooled to 10 C. and

a mixture containing 5 g. of Raney nickel in 50 ml. of

methanol was added. The reaction vessel was flushed with nitrogen and the mixture stirred for one hour. The reaction mixture was filtered and the methanol removed by evaporation in vacuo. The remaining acetic acid solution was diluted with one 'half its volume of water and then adjusted to pH 10 with 10% ammonium hydroxide solution. The resulting mixture was extracted with chloroform and the organic layer separated and washed with water. It was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue was triturated with 1:1 ethyl acetate and ether and the desired pure product recovered by filtration.

The corresponding 21-hydroxymethyl compound was similarly prepared from 2l-iodo-2l-hydroxymethyl-n pregnatriene-l1fl,l7a-diol-3,20-dione.

Example V.9a fluoro-ZI -methyl-A -pregnene-1 16,1 70a, 21 -trz'0l-3,20-aione A solution containing 500 mg. of 9a-fluoro-21-bromomethyl-M-pregnene-l1l5,l7ot,21-triol-3,20-dione in 200 ml. of acetone was cooled to 1'5" C. and a mixture containing 4 g. of Raney nickel in 50 ml. of acetone was added. The mixture was stirred for 15 minutes and filtered. The solvent was removed in vacuo and the residue triturated with 1:1 ethyl acetate and ether. The pure product was recovered by filtration.

The corresponding 21-hydroxymethyl compound was similarly prepared from 9a-fiuoro-2l-iodo-2l-hydroxymethyl-A -pregnene-l 1fl,17oc-di0l-3,20-Cii0l16.

Example Vl.9oc fluoro-ZI -methyl-A -pregnad ten-1 1,6, 1 701,21 -tr1'0l-3,20-di0ne A solution containing 500 mg. of 9a-fluoro-2l-bromoaaaaoaa identically prepared from 9u-fluoro-21-iodo=21-hydroxymethyl-A -pregnadiene-l lB,l7a-diol-3,20-dione.

Example VII.9oc-flu0r0-21-mthyl A -pregmrlriene- 1 3,1 712,2] -triol-3,20-dione A solution containing 500 mg. of '9a-fiuoro-2l-iodomethyl A -pregnatriene-l 1p,17a,2ltriol-3,20-dione in 200 ml. of ethanol was cooled to 10 C. and a mixture containing 15 g. of Raney nickel in 50 ml. of ethanol was added. The mixture was stirred for 24 hours and filtered. The solvent was removed in ,vacuo and the residue triturated with 1:1 ethyl acetate andether. The pure product.

was recovered by filtration.

The corresponding 2l-hydro'xyrn'ethyl carbon was similarly preparedfrom 9a-fiuoro-2l-brorno-2l-hydroxymethr- A'solution containing 500 mg. of 9a-bromo-2l iodo- -methyl-M-pregene-l113,17a,21-triol-3,20-dione in 200 ml.

of methanol was cooled to 15 C. and a mixturecontaining 15 g. of Raney nickel in 50 ml. of methanol was added.

The mixture was stirred for 1 hour and filtered. The sol-i vent wasremoved in vacuo and the residue triturated with 1:1 ethyl acetate and ether. The pure product was recovered by filtration. I i

The corresponding 21-hydroxymethy'l compound was similarly prepared from 9wbromo-2l-iodo-Zl-hydroxymethyl-A -pregnene- 1 1B, l7oc-di0l-3 ,2-dione.

Example IX .6a-fluar0-21 -methyl-M-pregr'zene 1 1,8,1 7a,.21-tri0l-3,20-dione A solution containing 500 mg. of I6-fluoro-2l-bromomethyl-h -pregnene-l1,8,17a,2l-triol-3,20-dione in 200 ml.

of absolute methanol was cooled to 0 C. and 5 g. of Raney nickel in 50 m1. of methanol was added. The mixture was stirredfor two hours, filtered and the methanol removed by evaporation. The residue was triturated=with 1:1 mixture of ethyl acetate and. ether. The product was removedby filtration. v

Example X .--6o:-flu0r0-2Z -hya'roxymethyl-A -pregnene- 1 1,6,1 7 a-dio l-3,20-di0ne A solution containing 500 mg. of 6afiuoro-2l-iodo-2lhydroxymethyl A pregnene-llb,l7a-diol-3,20-dione in 100 ml. of isopropanol was cooled to 10 C. anda mixture containing '4 g. of Raney nickel in 50 ml. of isopropanol (The Raney nickel has been previously was added. washed with water and then with diluted acetic acid t'o a pH of 7. It.was then washed with methanol, the meth-v anol removed and the Raney'nickel refluxed for 30 minutes in acetone.) The reactionmixture was stirred for minutes, filtered and the solvent removed in vacuo. The

desired product wastriturated with 1:1 ethylacetate and.

ether and recovered by filtration.

A solution containing 500 mg. of 16a-rneth'yl-2Lbromo-t M-pregnene-llB-l7a,21 trio1-3,20dione in 200 ml. of absolute methanol was cooled to 0 C. and'5 g. of Ra'ney' nickel in 50 ml. of methanol was-added. The mixture was stirred for two hours, filtered and the methanol removed byevaporation. The residue was triturated with a 1:1 mixture of ethyl acetate and ether. The product was recovered by filtration.

The corresponding 21-hydroxymethyl patent was simi-t 8 larly prepared from Y 21-iodo-1 6a-methyl-21-hydroxymethyl-A' pregnene-l- 16, l7okdi0l-3 ,20-dione.

Example X II ..1 6 [3,21 -dimethyl-A pregnene- 1 1118,1Zoz,21-tri0l-3,20rdi0ne A solution containing 500 mgppf lGB-methyl-Zl-bromo- A -pregnene l1,8,17a,21-triol-3,20-dione in'200 ml. of absolute methanol was cooled to'O" C. and 5 g. ;of Raney nickel in 50 ml; of methanol Wasadded. The mixture was stirred for two hours; filtered and the methanol removed by evaporation The: residue was triturated with a 1:1 mixture of ethyl acetate and .ether. The product was recovered by filtration. a

The corresponding ZI-hydroxymethyl patent was similarly prepared from 21-iodo-16,8rrnethyl-2l=hydroxymethyl-A '-pregnene-l 1 B,17a-diol,3,20-dione.

Example XlI I.-6a-chl0ro-21'- methyl-d -pregnene 1 1,8, I 712,21-tri0l-3',20 di0ne A solution containing 500 mg. of 6u-chloroa2l-bromomethyl A-pregnene-l 11,8,170:,21-lll'lOl-3,20rdl0fl6 in 200 ml.

of absolute methanol was cooled to 0 .C. and 5 .g. [of Raney niceklin 50 ml. of methanol was added. The mixture was stirred'fortWo hours, filtered and the methanol removed by evaporation. The residue was trituratedzwith 1:1 mixture of ethyl acetate and ether. The-product was recovered by filtration. I

The corresponding .2l-hydroxymethyl compound .was similarly prepared from 6a'-chloro- 2 1rbromo:2lrhydroxy methyl-M-pregnene-l 1B, 17a-diol-3 ,ZO-dione.

Example X I V1-'-'-21 '-methyLAM-pregnadiene- 115,17u,21-triol-3,20-dione' A solution containingmg. of 21-iodomethyl-A pregnadiene-l 1fl,17a,2l-trlOl-3 ,2 0-dione and mg. of

zinc dust wasstirred for 5 hours'at room temperature. An

additional. 100 mg. of zinc dust wa-s added and the stir.-

ring was continued for another 11 hours. The mixture. was filteredand the solvent evaporated in .vacuo. The

residue was taken up in 5 ml. of chloroform and the solu-.

tion washedwith 2 ml. of'water. The organic layer was 1 separated, dried over anhydrous sodium .sulfate,:filtered and the filtrate evaporated to dryness to leave the desired product as a residue. It was. purifiedby tritu'ration with ether.

The following, list exemplifies; certain of the compounds within the purview of this: invention .allepreparedusing the foregoing procedures. Iti-s given to avoid'urmecessary repetition of experimental. details; Ittshould be noted that. the compounds listed are all 2l-hydroxy compounds. Sim,-

ilar :ZI-hydroxyrnethyl compounds are tpreparedfrom the appropriate starting materials in accordance with theforegoing examples;:

It should be notedrthat in the. foregoing examples and in the following list no references are made to the two epimers of each compound which ,exist.

B-isomer. As stated above, these epi'r'ners arer'eadily sep-; arated, {for example, bypapencromatography. The 21- esters are ,separatedusing a $123 mixture of phlorofor n and benzene :as the mobile phase andformamide as the stationary phase; The 21-hydr'oxy compounds are separated using chloroform as the mobile phase and formamide as the stationary phase.

9a-chloro-21'-methyl-A -pregnene-11,3,l7a,2'1-triol-3,20a

dione 9a-iodo-2l-methyl-M-pregnene-l lfi,17a,21'-tI'iOl-3,20-

dione 9a-bromo 2l rnethyl-Al-pregnene-l 1,3,17a,21"-triol-3,20-

dione I 9u-ethoxy2l-methyl-Ahpregnenerl 1,8, l 7a, 2.l:-triolf-3 ,20-

dione v 21-rnethyl-A -pregnene-17a,2l-diol-3,l1,20.-trione.,

V v The name: of each compound, inaccordance withthe usual practice of. the art, is intended to encompass both the A- and; the

Specific yeasts applicable to the process include yeasts of the genus Saccharomyces, for example, Saccharomyces cerevisiae. The reduction is carried out by standard means known in the art such as subjecting the starting material to the action of a growing culture of the yeast or to a suspension of yeast cells. Reduction with alkali metal hydrides such as sodium borohydride, potassium borohydride, lithium borohydride or sodium alkoxy borohydrides is carried out by subjecting the propanoyl compound to the action of the selected borohydride in a reaction inert organic solvent such as the lower alkanols, lower alkyl amines or pyridine at a temperature of from about minus 40 C. to about 25 C. for a period of from about 2 /2 to about 8 hours. Although in theory, the equimolar portion of the, borohydride can be used, it is preferred to employ an excess of the reducing agent, say for example up to a 200% excess so as to insure complete reduction of the starting material.

The examples set forth below illustrate the application of both of these procedures to the preparation of the compounds of this invention.

Example X V.Yeast reduction A solution containing 500 mg. of ZI-methyI-Al -pregnadiene-l118,l7ot-diol-3,20,2l-trione in 100 ml. of ethanol is added to a stirred solution of 200 grams of sucrose in 1500 ml. of water. suspension containing 35 grams of Saccharomyces cerevisiae obtained by growing the microorganism in a suitable nutrient medium, filtering and drying the filtrate in 200 ml. of Water was prepared in a separate vessel and maintained at aproximately 40 C. At the end of a one-hour period, the steroid solution was added to this suspension and the reaction mixture stirred gently so as to maintain anaerobic conditions. The reaction is continued for from 56 to 72 hours. During this time, the pH is maintained within the range of from about 4.5 to about 5.0 by the addition of 1.5 N ammonium hydroxide. At the end of the first twentyfour hours, an additional 40 grams of sucrose and 7 grams of Saccharomyces cerevisiae suspension in 34 ml. of water and 2 ml. of ethanol is added. At the end of a forty-eight hour period, an additional 7 grams of yeast in 34 ml. of water and 2 m1. of ethanol is added.

The desired material is isolated by extracting the filtrate from which the insolubles have been removed with 4 separate 250 ml. portions of chloroform. The combined chloroform extracts are washed twice with volumes of 5% aqueous sodium bicarbonate and again with a volume of water. The organic layer is separated, dried over anhydrous sodium sulfate, filtered and the desired product recovered by evaporating the filtrate in vacuo.

E xample X VI.B0r0hyaride reduction A solution containing 186 mg. of 2l-methyl-A -pregnadiene-l1[3,l7a-diol-3,20,2l-trione in ml. of meth anol was prepared. To this solution there was added a mixture containing 13.3 mg. of sodium borohydride in 3.6 mlfof methanol and the mixture was allowed to stand at from 0 to 5 C. for 3 hours. The excess reducing agent was decomposed by the dropwise addition of dilute acetic acid. The mixture was filtered and the solvent removed in vacuo. The residue is taken up in chloroform, washed with water, the organic layer dried over anhydrous sodium sulfate, filtered and the desired product recovered by removal of the solvent in vacuo.

The product is best purified by conversion to the 21- acetate which crystallizes from solution quite readily. This may be accomplished by taking up the residue in a mixture containing 2 ml. of pyridine and 1 ml. of acetic anhydride. The mixture is then allowed to stand for 12 hours and the excess anhydride decomposed by the addition of water. The water precipitates the product and it may be recovered by filtration. It is, however, best to recover the product by extracting the mixure with chloroform. The resulting chloroform solution is washed successively with water, 2 N hydrochloric acid and again with water, the organic layer is dried over anhydrous sodium sulfate filtered and the solvent removed in vacuo to leave the product as a residue which is purified by trituration with ether.

Compounds within the purview of this invention having an ll-keto group are prepared by oxidation of the ll-hydroxy group. It will be recognized by those skilled in the art that in certain instances it will be possible to use starting materials already containing an ll-keto group. Alternatively, the final product itself may be oxidized. In all instances it is preferred to protect hydroxyl groups in other than the ll-position by esterification prior to oxidation of the ll-hydroxyl group. To do otherwise may lead to mixtures of products as a result of simultaneous oxidation of hydroxyl groups. The oxidations are effected by procedures well known in the art, including, for example, the use of chromium trioxideor the chromic acid-pyridine complex. A variety of esters of the foregoing 16- and 2l-hydroxylated compounds as well as esters of the 2l-hydroxymethyl compounds are prepared in accordance with standard esterification procedures. The esters prepared include the formates, acetates, propionates, propenoates, butyrates, decanoates, hemisuccinates, hemiglutarates, toluates, citrates and cyclohexylpropionates. In those compounds having both a l6-hydroxyl and a 2l-hydroxyl or 21-hydroxymethyl group, the esters prepared generally contain the same acyl group at both positions. There is no particular advantage in preparing diesters with diverse groups at the 16-and 2l-positions, but if desired these can be prepared either by using 16-esterified steroid aldehyde as the starting compound or by careful hydrolysis and re-esterification using procedures well known in the art.

Alkali and alkaline earth metal salts of the acid esters are prepared by reaction of the said acid esters with the hydroxides or carbonates of the selected metal in accordance with standard procedures. These products have the advantage of increased solubility in water compared to the other compounds of this invention.

The following example is illustrative of two of the methods used to prepare the 16,17-acetonides of'this invention, including those prepared from the compounds of the previous examples. Those prepared by these methods include the acetals and ketals from acetaldehyde, propionaldehyde, butyraldehyde, acetone, diisopropyl ketone, methyl ethyl ketone and di-n-butyl ketone.

21 methyl A pregnadiene 1l,8,l6u,l7a,21- tetrol-3,20-dione mg.) was taken up in 100 ml. of acetone which had been previously dried overanhydrous potassium carbonate. To this mixture,-there was added 495 mg. of anhydrous copper sulfate and the mixture was stirred at 2030 C. for two days. The mixture was filtered, dried over anhydrous potassium carbonate, again filtered and the excess solvent removed in vacuo. The residue was triturated with ether containing a few drops of acetone and the desired .product recovered by filtration.

9oz fluoro 21 methyl A pregnadiene 115,16, l7a,2l-tetrol-3,20-dione (350 mg.) was taken up in 25 ml. of-propionaldehyde containing two drops of concentrated hydrochloric acid. The mixture was refluxed for 5 minutes and allowed to stand at 2030 C. for 8 hours. The desired product was precipitated by the addition of water and isolated by filtration.

As stated above, compounds of this invention are also prepared by a procedure which permits the preparation of both the A- and the B-isomer in pure form. The synthetic scheme set forth belowillustrates the applicability of ,thelproeess, to ,the preparation of some. ofthe 'wmii vnd tg qlh Y nt -f' om... he n wn, cm qu theprocedure of Peterson et a1; as described in ;the.

Journal of the American Chemical Society, 'vol. 74,: page 5933*- (1952;). The resulting compoundis oxidized with periodic acid-to convert -the 'a-hydroxyacetyl group at the' lm position to acarhoxyligroup. Oxidation of the llu-hydroxyl group to form- CompoundTIIy 1601,17- epoxy-B,1'1-diketoM-etioeholenic .acid, iseffected: using chromicl oxideiuacetic acid-. accordingtto standard procedures,;well known! inzthe; art. Other; oxidizing agents; for.- example, .the chromicr. acid-pyridine complex canv be ompound 1l ehydroxy etl7 ne oxy-3dew-A te m- I similarly employed. The ,acidis next conyerted'to-an acid chloride? by the intermediate formation ofr a sodium salt'w-ith a suitable'base such. assodium-rhydroxide fol: lowed byreaction'with oxalyl chlo'ridez. The compound so formed, 5' Compound :IILs is COIlYCItCdntO a chloro ketone, 21-methyl-2l-chloro-16a,l7a-epoxywAt-pregnenef 3,l1,20;trione, Compound, 1V by reaction a with diazoethane followed by treatment with ,hydrogen chloride in' ether. Treatment of: Compound .IV with potassium. acetate in acetone affords a mixture of :bothv possibledr asterioeisomers of- 2l-methyle2leacetoxye16a,,l.7a-epoxy- A -.pregnene-3,11,2O-trione and fthese are separated ..by

chromatography; forexample on a synthetic silicate of the. class described in US. Patent No.. 2,393,625 such as Florisil available: from the. Floridin companys ofYIfallahassee, Florida, and=,each isomer; is thereafterseparately should be hydrolyzed to an alcohol andtheketone groups at the ;3- and ;the 20-positions should Ebe protectedby forming ethylene ketals by reaction withethylene glycol. The diketal is reduced, lithe ketal groups removed-by acid hydrolysis; andrthe 21rhydroxy groupreacetylated using the -usual= procedures. Dehydrogenation of ithis acom-v pound with selenium. dioxide produces :2 1.1methy1-A pregnadiene-l 1fi,17a,2l-triol-3,20 dione ZI-acetate. Al-t ternat ively, the double bond 1 can. .be directly 7 introduced to produce, 2l.-methyl A -pregnadiene-l7a,2l-diol-3,11, 2Q-trione, one of the compounds of'thisinvention. This reaction is illustrated in the examples.

As. an alternative to the above describedprocedure, an ll-desoxy co1'r1pound--,- that; is, 16o;,17uepoxy:3-keto-A etiocholenic acid can be. carried througha.;similar.series of reactions Hild' lhQ-llfi hYdl'DXYl group introduced .using Curvularia lunqta in accordance with theprocedure of Shull -et. filJtdQSCflbBddlltthQ Journal of'the;American Chemical Society, vol. 7 7', page 763 a 195 5) The compound 16a,lfla-epoxy-A epregnenerl la,2 l,diol- 3,20-dione (M.P. 214 to 216 G2) was prepared: by in- 21'-a'cetate withRhizopus nigricans according to the pro cedure. of Peterson ;et a1.-- and 2.20 grams ofrthis material were taken up in 400 m1. of hot dioxane and the mixture.

clarified :bythe filtration. 7 .To the Vfiltrate,.there wasladded ZO-grams of :periodic: acidtjin 400 m1. of water and, the resulting mixture was..-allowed-toz stand for l6 hours at 25C. Atthe; end of -thispe rio,d,;the mixture was stirred i into :1600 ml. of ice cold water and the ,wholeistirred for:

another, :30 minutes.

The; desired product precipitated 4 and'wasrecoveredbyrfiltration. The product waspurie fied by.=recrystallization fromzethanoh} MP. 216 102117.". C. (d.'),, .M EtOH ,=.24 2 me, e=15,600.-'

Example XVIII -1 6a,! 7u-epoxy-3,1 l-'diket0-A etiochqlen ic. acid- A solution was prepared containing lO grams of. the compound oftthe-previous examplednSOQml; of glacial f acetic acid; To thisfsolution therewas addeddropwisewith-stirring overa periodof-40 minutes, ml ofan aceticv acid solution 'containing :1.1 equiyalentsofich ro-r mium; trioxide. The mixture was stirred at 25"? C, reran additional hour. The resulting solution was added to 1800 ml. of water at C. and filtered. The filtrate was extracted three times with 250 ml. portions of chloroform and the chloroform extract washed twice with equal volumes of water, dried over anhydrous sodium sulfate, filtered and the desired product recovered by evaporation of the solvent in vacuo. For purification, the residue was first taken up in dilute sodium hydroxide. It was then filtered and the pure acid precipitated by the addition of dilute hydrochloric acid. The product was recovered by filtration.

Example XIX.-16a,17ot-ep0xy-3,11-diket0-A etiocholenic acid A slurry was prepared by the addition of 20 grams of the product of the previous example to 140 ml. of water. The solution was stirred and 42.5 ml. of 1.3 N sodium hydroxide was added. The mixture was filtered and the filtrate freeze dried to give the desired product.

Example XX .-1 6 ,1 7a-ep0xy-3J1-diket0-A etiocholenyl chloride The sodium salt (21.8 grams) prepared in the previous example was taken up in 600 ml. of benzene and dried by the distilling of 200 ml. of the benzene and water azeotrope at atmospheric pressure. The resulting slurry was maintained at approximately 5 C. while 40 ml. of oxalyl chloride was added in two 20 ml. portions. The second portion was not added until the foaming resulting from the first addition had subsided. The mixture after the second addition was maintained at approximately 5 C. and stirring was continued for another 30 minutes while the temperature was permitted to slowly increase. The mixture was clarified by filtration and the filtrate evaporated in vacuo. The residue was dried to remove the benzene and taken up in 1.3 N sodium hydroxide, filtered and the filtrate adjusted to pH 2.0 with 3 N hydrochloric acid. The desired product precipitated and was recovered by filtration.

Example XX I .2] -methyl-21 -chl0r0-1 6 a,1 7a-epaxy- A -pregnerte-3,11,20-tri0ne A benzene solution containing 20 grams of the acid chloride synthesized in the previous example was mixed with an excess of diazoethane in 600 ml. of ether prepared in accordance with the standard procedures and the mixture was stirred for one hour at from -15 to 10 C. At the end of this period, 400 ml. of an ethereal solution containing grams of hydrogen chloride was added at -5 C. and the mixture stirred for approximately 5 minutes. The solution was extracted three times with equal volumes of ice cold water, once with an equal volume of 5% aqueous sodium bicarbonate and again with an equal volume of water. The organic solution was dried over anhydrous sodium sulfate, filtered and the desired product recovered by removal of the solvent in vacuo.

Example XXII. 21 -methyl-1 6a,] 7a-ep0xy-A -pregnene- 3,11,20-tri0ne 21 -acetate (a mixture of diaslerioisomers) The product obtained in the previous example (7.236 grams) was taken up in 3.66 liters of acetone and to this mixture there was added 10.35 grams of potassium bicarbonate. The mixture was then heated to approximately 50 C. and 6.15 ml. of glacial acetic acid was added. It was refluxed. for 10 minutes and 5.15 grams of potassium iodide was added. The mixture was then refluxed for 16 hours and concentrated to a volume of approxi mately 100 ml. in vacuo. To the concentrate, there was added 300 ml. of water and the resulting solution extracted three times with 300 ml. portions of chloroform. The combined chloroform extracts were washed successively with a 200 ml. portion of water, a 200 ml. portion of 5% aqueous sodium bicarbonate and an additional 200 ml. portion of water. The chloroform solution was evaporated to dryness in vacuo.

26 Example XXIII.-Separati0n 0f dzasterioisomers A total of 18.39 grams of the compound synthesized in accordance with the procedure described in the previous example was taken up in benzene and placed on a Florisil column which formed a 20 inch bed of 2 inches diameter. The column was eluted with 4 liters of benzene (fraction 1), 5 liters of benzene-10% ether (fraction 2), 2.5 liters of ether (fraction 3), 1.5 liters of chloroform (fraction 4), 3.0 liters of 90% chloroform-10% ethyl acetate (fraction 5), and 2 liters of ethyl acetate (fraction 6). Each of the fractions was separately concentrated to dryness in vacuo and the residue purified by triturating with ether. The A-isomer was found predominantly in fractions 1 and 2. The B-isomer was found predominantly in fractions 5 and 6. Fractions 3 and 4 contained mixtures of the isomers and these could be separated by further chromotography.

PHYSICAL CONSTANTS I. 21-methyl-16u,l7a-epoxy-A -pregnene-3,11,20-trione 21- acetate A-isomer:

M.P.=173174 C. [a] =+180.1 (diox.) h =237j mp, e=l5,700 Analysis.Calcd. for C H O C, 69.54; H, 7.30. Found: C, 69.09; H, 7.22.

II. 21-methyl-16a,l7a-epoxy-A -pregnene-3,11,20-trione 21-acetate B-isomer M.P.=204-205 C. [a] =+171.5 (diox.) h =2375 mp. e=l5,800 Analysis.Calcd. for C H O C, 69.54; H, 7.30. Found: C, 69.96; H. 35.

Example XXI V.-1 6,3-br0m0-21 -methyl-A -pregnene- 1 7a,21-di0l-3,11,20-frione 21-acelate- To a suspension containing 3.05 grams of the 21-acetoxy compound in 23 ml. of glacial acetic acid there was added 7.6 ml. of 30% hydrogen bromide solution in glacial acetic acid. The solution was allowed to stand at 25 C. for one hour. To this solution at 0 C., there was added 300 ml. of water. The desired product precipitated and was recovered by filtration.

Each of the isomers was subjected to the foregoing treatment.

PHYSICAL CONSTANTS I. 1'6,B-bromo-2l-methyl-A -pregnene-l7a,2l-diol-3,11,20-

trione 2l-acetate A-isomer:

M.P.=186187 C. (d.) [a] =-|167.9 (diox.) h =238 ma. e=15,800 Analysis.Calcd. for C H O Br: C, 58.18; H, 6.31; Br, 16.13. Found: C, 58.30; H, 6.36; Br, 16.32.

II. 16,8 bromo-2l-methyl-A -pregnene-l7a,21-diol-3,l1,20-

trione 21-acetate B-isomer:

M.P.=222-223 C. (d.) [a] =+l32.1 (diox.) A =238 m e=15,900 Analysis.-Calcd. for C H O Br: C, 58.18; H, 6.31; Br, 16.13. Found: C, 58.48; H, 6.34; Br, 16.23.

Example XXV.-21-methyl-A pregnene-1 7a,21-di0l 3,11,20-tri0ne 21 -acetate A mixture containing 1 gram of bromohydrin and 10 grams of Raney nickel in ml. of methanol was stirred Found: C, 68.86; H, 7.75.

acetate and ether.

treatment.

in a 'nitrogen'atmosphere'at25 Clfo r 41161155. The

mixture was filtered and .concentratedto drynesswThe I 'residue was, taken up in 50 ml. of chloroformfandrthe chloroform solution washed twic'e'with 30 mlwportionswof The organic layer was se'parated,.dried over anwater. hydrous sodium sulfate,tfiltered andiconcentrated todryness.

treatment.

PHYSICAL CONSTANTS I. '21 methyl A -pregnene-17u,2l-diol 3,11

acetate.

A-isorner:

M.P.=179180 C. I [oc] =+169.1 (diox.) k =238mu e=155400 -An'alysis.Calcd; for C H 0 ,ZG-trione. 12 1- Example X X VI .-21 -methyl-A -pregna-diene-J 7.x,2 1- 1 did-3,1 1',20-tr'i0'ne 21 -acetate A total of 1.0 gramof the cornp ound' prepared in accordance with the procedure describedfin 'the previous I example was taken upin 50ml. of tertiary 'amyl alcohol "containing 0.5 ml; of glacial acetic acid and1.1'-fgrarns.of

selenium dioxide was added. Thesolutio'n was refluxed for 20 hours.' It was then :filtered and'the filtratew'ashed successively with 'equali volumesof water, 110% aqueous sodium -bisulfite solution (3 times) and finally .with two portions .of Water. The organic solution was evaporated The residuetriturated with a mixture'of'ethyl ace-' mm and ethenfiltered anddrie'd. 1

Each of theisornerswas subjectedto the foregoing to dryness in vacuoand theresidue .triturated with ethyl Each of the isomers was subject'ed'to the foregoing PHYSICAL CONSTANTS' v I. 21-methy1-A pregnadiene-.17a,2l-diol-3,11.20'- trione 2 1-acetate A-isorner:

M.P.=182-183 C. [a] =+145.4 (diox) h H I R =239 III/L I e=15,300 v Analysis.Calcd. for C H 6O3:

(5,169.54; 11.17.30; F0und:C,'68.77;H,' 7.09.

v The .productwas purified Eby 'recrystallization fromriiethanol containing a smallportion i" I of activated charcoal.

VIII. Qcx-fiIlODO-Z l--methyl-A apregnene-H 3;171 ,23

xggx=24z m (15,700)

r IX. 9u-fluoro-2 lz-rnethyleAl t-pregnadiene- 1.15; 171152 1 -t rio1-.

The following.table presents theiphysical coristants-..-of

some of the compounds within thepurview of thisdnvention.. i

'chloroacetate Example VII.9a-fluoro-21methyl-A -pregnadiene- 115,] 701,21 -tril-3,20-di0ne 21 -diethyl-amin0acetate and related compounds 9m-fluoro-2l-methyl-A -pregnadiene-l 113,17oc,21 triol- 3,20-dione, B-isorner, 30.22 g., is dissolved in 120 ml. of dimethylformamide and 10.5 ml. of pyridine. The mixture is cooled to 7 C. and 10 ml. of chloroaoetyl chloride is added dropwise during 30 minutes. The mixture is allowed to come to room temperature, 23 C., then is poured slowly into 500 ml. of 1N sulfuric acid; during the addition, the suspension is stirred and is maintained at 10 C. The crystals, which precipitate, are removed by filtration and are washed with water until the washings are neutral. After drying in a vacuum, the product, 90: fluoro 21methyl A -pregnadiene-11fl,17a,21-triol- 3,20-dione 21-chloroacetate, weighs 38.4 g. Recrystallization from acetone and water mixtures affords an analytically pure sample, M.P. 227-228 C., A MeOH, 238 m (e=15,600).

The procedure is repeated substituting for the 90:- fluoro-steroid, a stoichiometrically equivalent amount of 6a,9a-difluoro-21-methyl A pregnadiene- 11B,17u,2ltriol-3,20-dione, B-isomer. There is obtained 6a,9a-difluoro-21-methyl-A -pregnadiene-l1,8,17a,21 triol-3,20- dione 21-chloroacetate.

The 9oz fluoro-21-methyl-A -pregnadiene-l 113,17oc,21- triol-3,20-dione 21-chloroacetate, 4.3 g., is suspended in 50 ml. of diethylamine and the suspension is refluxed under nitrogen for 1.5 hours. The excess diethylamine is evaporated in vacuo and the residue is dissolved in 50 ml. of chloroform. The chloroform solution is washed with 15 ml. of 4% aqueous sodium bicarbonate, and twice with 15 ml. of water. -The chloroform layer is separated, is dried over anhydrous sodium sulfate and the solvent is evaporated. The crystalline residue, 5.4 g., is recrystallized from 75 ml. of acetone. The crystals of 9a-flu0ro-2l-rnethyl-A -pregnadiene l1fi,l7a,21 triol- 3,20 -dione 21-diethy1aminoacetate after two recrystalliiations from chloroform-hexane (1:2) melt at 191.5-

The hydrochloric acid addition salt of 9a-fiuoro-21- methyl-A -pregnadiene-l lB,17a,21-triol 3,20 dione 21- diethylaminoacetate is prepared: a saturated solution of hydrogen chloride in ether, 150 ml., is added to a solution of 45.8 g. of the said diethylamino acetate in 2.5 liters of acetone'at 40 C. The suspension is concentrated at 45? C. to about 0.5 liter, is cooled to C. and is'filtered' The crystals are washed with acetone and 42.6 g. of tail solids are obtained; after drying, M.P., 22l222.5'.' A more pure product is obtained after further crystallization from ethanol and hexane and finally, from acetone, M.P., 223224 C.', with decomposition; Am, MeOH, 239 m t'(e=14,630); a +1235 (C,"2.04; MeOH). By the-same procedure, starting with 6oz,9oc-difiu0IO-21- methyl-A -pregnadiene-I1 3,17a,21-triol- 3,20 dione 21- there are prepared 6u,9'a-difluoro-2lmethyl-A 'pregnadiene-l1fi,17a,21-triol ZI-diethyla'minoacetate and the hydrochloric acid addition salt thereof.

The A-isomers of these compounds are prepared in the same manner described in detail for the B-isomers,

above. Example XX VIII .-Pr eparati0n of 21 amin0z zcyl esters of Qu-fluoro-Zl -methy-l--A -pregnadiene-Z 1 3,1Zot,21 friol- 120-dione and related compounds '1 The procedure of Example XXVII 'is, repeated substituting for diethylamine, stoichiometrically equivalent I amounts of dimethylamine, piperidine, morpholine and di-n-butylamine. In the case of dimethylamine, a pressure vessel is used.

The following products are obtained:

B2 I V l3: K wherein Rf is selected from the group consisting of hydrogen and-methyl;"R is selected frorn'thegroup consist' ing of hydrogen, fluorine, chlorine and methyl; R is selectedfrqm the group consisting of hydrogen and hy- *drozgyl;-'-R is selected from the group consisting o'fyhydrogen and-acyl;saidacyl; group being derivedefrommonoand dicarboiryliczacids containingmp to ten'carboniamms;

" ligiisselectedfrom -the--group-cons istin g of .ORe

wherein R is an acyl group containing only carbon,

gen; alkali and alkaline earth metal salts of, said acylated compounds wherein the -acyl group is derived from a lidicarboxylic acid; acid additionisaltslof said acylatedcompounds' whe'reinithe acyl groupnsiderived from an amino carboxylic-; acid and 16,17-acetonides ofz'jsaid 16,17-hydroxylated compounds wherein theiacetonide moiety con-p tains from'two to nine-carbon atoms. 1

2. A pharmaceutical composition comprising a compound ascIaimed, in elaim 1 together with a p harm'aceu-v tically acceptable'carrier.

3. A process for the preparation of 2i1 '-hydroxy;andr

21-hydroxymethy1 compounds which comprises reacting a compound having the formula:

CH3 CH3 CHzZ (IJHiZ CHOH (IZHOH atoms: being. gide'rivedtfrom rn'ono- =-and: dicarboxylic; acids '1 containing-mp to iten' carbon atoms;- with hydrogenv in "the (;pre sencei of {a Raney nickel ,zcatalyst inea reaction inert wherein-R is selectedirom the; group; consisting ofthydro- :ggen and methyl; ;'1 is selected from the group; consisting of=hydrogen, fluorine, chlorine and methyl; R3fi$$ltd :f m the r gr oupggconsisting 1 of uhyd siswselected from jhe gr oupgconsisting-of:

-swherein- R5 isvi'an acylQgroupgX' is; selectedzfrom the group .:,-Z is; selected fronwth'ev; group consisting v ofg iodine gand bromine atoms andX;is selected-fro he group I yting q of i'keto "and ;3hydroxy1; at leas't 'iof -R ;,R ,;;R' "and ggthez additionalzisubstituent ion1a hydrogen-subs tuted gnumber sixteen carbon atom always-being rhydn j .acylzgrioupecontaining only tcarbonghydrogeng and ygen organic; solyent'at;a temperature; below .309? C; I

' i=4. ;A:'compoundz;zselected from the groupygconsisting of :the

115,17a,2l-triol-3,20-dione and the 21 acyl esters-thereof whereintheacyl group is derivedj frommonoand dican boxylic' acids containing "up to ten carbon atom's.

51 A compoundvselec'ted from "the group consisting of the' B-isomer, of 9 m-fluoro-2l rnethyl n -pregnadiene- L 17B,17 t,21;triol 3,20:dione=andithe ll-acyl esters thereof wherein ah acvl s qu i d r mfmn n a is boxylii; acids containing upFtQ tenCarbOn atoms.

rogenth andqhydroiryl;

consistant 33 34 6. A compound selected from the group consisting of diene-l1B,17a,21-tri0l-3,20-dione and the 21-acyl esters the A-lsomef 0f Y -P thereof wherein the acyl group is derived from monoand i zl'acyl esters dicarboxylic acids containing up to ten carbon atoms. thereof wherein the acyl group 18 derived from monoand dicarboxylic acids containing up to ten carbon atoms. 5 No references cited.

7. A compound selected from the group consisting of the B-isomer of 6a,9a-difluoro-21-rnethyl-A -pregna- LEWIS GOTTS, Pnmary Exammer- 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAS:
 2. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND AS CLAIMED IN CLAIM 1 TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE CARRIER. 